Complement receptor 2 (CR2/CD21) is the strongest candidate gene for lupus susceptibility in the Sle 1c lupus susceptibility interval of the NZM2410 mouse model of lupus, based on structural and functional alterations in its protein products. In humans, CR2 is located in a syntenic genetic interval that is also linked and associated with lupus susceptibility. A single-nucleotide polymorphism (SNP) in the 5' untranslated region (UTR) of the human CR2 gene reduces gene transcription and alters transcription factor binding. A three SNP haplotype consisting of this SNP plus two other CR2 SNPs is associated with lupus susceptibility in Caucasian and Chinese cohorts containing SLE patients and their parents. The project outlined in this proposal will address the hypothesis that CR2 is a lupus susceptibility gene in humans. The specific aims are to identify the CR2 haplotype blocks that are associated with lupus in different ethnic groups; to fully characterize the effects of the 5'UTR SNP on gene transcription; to determine whether additional SNPs in the CR2 gene alter CR2 function; and to demonstrate the effect of individual SNPs and SNP haplotypes on lupus pathogenesis. First, SNP analyses will be performed in cohorts of African-Americans, Caucasians, Chinese, and Hispanics to define haplotype blocks and their linkage and association with lupus in these four ethnic groups. In concurrent studies, the SNPs in the coding and regulatory domains of the CR2 gene will be examined for functional effects. In the case of the SNP in the 5'UTR, for which a functional effect has already been identified, elaborate studies will be performed to characterize how it alters gene function. For the other SNPs in regulatory and coding domains, a more general evaluation to determine functional significance will be performed before delving more deeply into the mechanisms by which these SNPs may alter gene function. In addition, bacterial artificial chromosome (BAG) transgenic mice expressing individual CR2 SNPs as well as CR2 SNP haplotypes on a murine CR2-deficient background will be generated in order to determine whether specific alleles protect from or promote disease development. These studies will advance our understanding of the role of CR2 as a human lupus susceptibility gene and provide insight into the mechanisms by which it contributes to disease development, leading potentially to CR2-targeted therapies for SLE. [unreadable] [unreadable] [unreadable]